Abuse-resistant oral dosage forms and method of use thereof

ABSTRACT

An opioid-antagonist oral dosage form which does not release a therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, but whereby a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist. An embodiment of the oral dosage form includes an opioid-antagonist layer coated onto a biologically inert pellet, and a non-releasing membrane coated onto the opioid-antagonist layer. Optionally, the oral dosage form can also include an opioid agonist, such that a method of preventing the abuse of an oral dosage form of an opioid agonist is provided by forming the oral dosage form including an opioid agonist and an opioid antagonist.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 10/409,992 filed Apr. 8, 2003, the content of whichis herein incorporated by reference in its entirety.

TECHNICAL FIELD

The invention relates to an abuse-resistant substance, such as anopioid-antagonist, oral dosage form which does not release the opioidantagonist in a therapeutically effective amount when the oral dosageform is orally administered to a human being, but whereby a physicalalteration of the oral dosage form results in a release of the opioidantagonist in an amount effective to prevent the abuse. The oral dosageform can further include an abusable substance, such as an opioidagonist, in order to prevent the abuse of the opioid agonist. Apreferred embodiment of the invention includes naltrexone as theabuse-resistant substance in an oral dosage form.

BACKGROUND

Opioid agonists, or opioids, are drugs which are used primarily asanalgesics. Opioid agonists act on stereospecific receptor sites in thebrain, as well as in other parts of the body, which presumably regulatethe feeling and perception of pain. Examples of opioid agonists include,but are not limited to, oxycodone, morphine, hydrocodone and codeine.Although they are effective in reducing the perceived pain by a patient,opioid agonists also have the characteristic of possibly beingphysically and psychologically addictive to the patient if usedrepeatedly over an extended period of time. Thus, the potential foraddiction to or abuse of such drugs is an issue of concern wheneverprescribing such drugs as analgesics.

For example, oxycodone is an opioid agonist which has a high potentialfor abuse. Oxycodone is most often administered orally, and iscommercially available in a controlled-released form known as Oxycontin™(Purdue Pharma). However, the controlled release aspect of an Oxycontin™dosage form can be bypassed by an abuser by, for example, crushing orgrinding up the dosage form, and then eating or snorting the crushed orground-up Oxycontin™ dosage form. Thus, in this way the abuser is ableto receive a relatively large single dose of the oxycodone, resulting ina euphoric “high” being experienced by the abuser.

Opioid antagonists are those drugs which serve to neutralize or blockthe euphoric or analgesic effect of an opioid agonist. For example,opioid antagonists are often employed to block the euphoric or analgesiceffects in individuals who have overdosed on an opioid agonist, or as adaily treatment drug in individuals who are addicted to an opioidagonist. It is thought that the opioid antagonists act on and competefor the same stereospecific receptor sites in the brain as the opioidagonists, and thereby neutralize or block the resulting-analgesic oreuphoric effects of the opioid agonist.

Thus, there have been previous attempts in the prior art to produceformulations and methods concerned with reducing the abuse potential ofopioid agonists. For example, U.S. Pat. No. 6,228,863 to Palermo et al.describes a method of preventing the abuse of opioid dosage forms bycombining an orally active opioid agonist with an opioid antagonist intoan oral dosage form which would require at least a two-step extractionprocess to separate the opioid antagonist from the opioid agonist.According to Palermo et al., the oral dosage forms described therein hadless parenteral and/or oral abuse potential than that of the prior artoral dosage forms.

In addition, U.S. Pat. No. 6,277,384 to Kaiko et al. describes oraldosage forms including combinations of opioid agonists and opioidantagonists in ratios which are analgesically effective whenadministered orally, but which are aversive in a physically dependentindividual. According to Kaiko et al., the oral dosage forms describedtherein had less oral abuse potential than that of the prior art oraldosage forms.

Furthermore, U.S. Pat. No. 5,236,714 to Lee et al. is directed to anabusable substance dosage form having a reduced abuse potential. Lee etal. disclose compositions and dosage forms for administering abusablesubstances wherein the therapeutic effect of the abusable substance willnot be diminished, although the abuse potential of the abusablesubstance will be diminished. Specifically, topical compositions forapplication to a patient's skin or mucosa are disclosed including anabusable substance present in a form which is permeable to the skin ormucosa to which the composition is to be applied, and an antagonistpresent in a form which is impermeable to the skin or mucosa to whichthe composition is to be applied, such that if an attempt were made toabuse the composition by administering it through another bodily portal,the antagonist would prevent the occurrence of the abusive effect byproducing its antagonistic effect. In addition, Lee et al. disclosedosage forms comprising a drug reservoir composition including anabusable substance and at least one antagonist enclosed within anabusable substance releasing means, wherein the abusable substance ispresent in a form which is permeable through the releasing means and theantagonist is present in a form which is impermeable to the releasingmeans. As with the topical composition, Lee et al. disclose that if anattempt were made to abuse the drug reservoir composition by removing itfrom the dosage form and administering it through another bodily portal,the antagonist would prevent the occurrence of the abusive effect byproducing its antagonistic effect. The dosage forms of Lee et al.include a single abusable substance releasing means which controls therelease of both the abusable substance and the antagonist.

However, there is still a need in the art for an improved oral dosageform of an opioid antagonist which would reduce the abuse potential ofan opioid agonist.

SUMMARY

An embodiment of the present invention is directed to anopioid-antagonist oral dosage form wherein the opioid antagonist doesnot release unless the oral dosage form is crushed or ground up, therebyantagonizing the opioid effect of an opioid agonist.

An embodiment of the oral dosage form of the present inventioncomprises: a biologically inert pellet; an opioid-antagonist layercoated on the biologically inert pellet, wherein the opioid-antagonistlayer comprises a therapeutically effective amount of an opioidantagonist; and a non-releasing membrane coated on the opioid antagonistlayer, wherein the non-releasing membrane comprises a water-retardantpolymer and may contain a lubricant; wherein the oral dosage form doesnot release the therapeutically effective amount of the opioidantagonist when the oral dosage form is orally administered to a humanbeing, and wherein a physical alteration of the oral dosage form resultsin a release of the therapeutically effective amount of the opioidantagonist.

In another embodiment of the invention, the oral dosage form can alsoinclude a second pellet comprising an opioid agonist, and/or other painrelievers and anti-inflammatory agents.

In a further embodiment of the invention, the oral dosage formcomprises: an opioid-antagonist formulation, wherein theopioid-antagonist formulation comprises a therapeutically effectiveamount of an opioid antagonist; and a non-releasing membrane coated onthe opioid-antagonist formulation, wherein the non-releasing membranecomprises a water-retardant polymer and may contain a lubricant; whereinthe oral dosage form does not release the therapeutically effectiveamount of the opioid antagonist when the oral dosage form is orallyadministered to a human being, and wherein a physical alteration of theoral dosage form results in a release of the therapeutically effectiveamount of the opioid antagonist.

The invention is also directed to a method of preventing the abuse of anoral dosage form of an opioid agonist. An embodiment of the method ofthe invention includes the forming of an oral dosage form by combining:(1) a first type of pellet comprising an opioid agonist; and (2) asecond type of pellet comprising: a biologically inert pellet; anopioid-antagonist layer coated on the biologically inert pellet, whereinthe opioid-antagonist layer comprises a therapeutically effective amountof an opioid antagonist; and a non-releasing membrane coated on theopioid antagonist layer, wherein the non-releasing membrane comprises awater-retardant polymer. The oral dosage form does not release thetherapeutically effective amount of the opioid antagonist when the oraldosage form is orally administered to a human being, and a physicalalteration of the oral dosage form results in a release of thetherapeutically effective amount of the opioid antagonist.

Another embodiment of the method of the invention includes coating anon-releasing membrane onto an opioid-antagonist formulation, andcoating an opioid-agonist layer onto the non-releasing membrane to forman oral dosage form, wherein the opioid-antagonist formulation comprisesa therapeutically effective amount of an opioid antagonist, thenon-releasing membrane comprises a water-retardant polymer, and theopioid-agonist layer comprises an opioid agonist. The oral dosage formdoes not release the therapeutically effective amount of the opioidantagonist when the oral dosage form is orally administered to a humanbeing, and a physical alteration of the oral dosage form results in arelease of the therapeutically effective amount of the opioidantagonist.

In addition, a further embodiment of the method of the invention alsoincludes adding other pain relievers and/or anti-inflammatory agentswhen forming the oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of the in vitro release of naltrexone hydrochloridefrom an embodiment of the oral dosage form of the present invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention, as disclosed and described herein, provides anovel oral dosage form of a therapeutically effective amount of anopioid antagonist which does not release when orally administered to ahuman being, but which does release upon a physical alteration of theoral dosage form. That is, if the oral dosage form of the invention isorally administered to a human being, then the therapeutically effectiveamount of the opioid antagonist is not released from the oral dosageform, and thus an opioid agonist will have its intended analgesic effecton the human being. As used herein, the phrase “a therapeuticallyeffective amount of an opioid antagonist” refers to that amount of theopioid antagonist which is sufficient to antagonize the opioid agonistand thus effectively neutralize the intended analgesic effect of theopioid agonist. Thus, when orally administered to a human being,although the oral dosage form of the invention may release a negligibleor inconsequential amount of the opioid antagonist, it will not releasean amount to antagonize the opioid agonist and to neutralize itsintended analgesic effect.

However, if the oral dosage form of the invention is physically alteredin any way, such as by crushing or grinding of the oral dosage form,then the therapeutically effective amount of the opioid antagonist willbe released. That is, as the non-releasing membrane of the oral dosageform is rendered ineffective by physical alteration, the opioidantagonist will no longer be effectively coated by the non-releasingmembrane and the therapeutically effective amount of the opioidantagonist will thereby be released. Therefore, the opioid agonist willbe antagonized by the opioid antagonist and the intended analgesiceffect of the opioid agonist will be effectively neutralized, reduced orblocked. Thus, if an individual were to crush and grind up the oraldosage form of the present invention in an attempt to take itparenterally, or orally, or by snorting it through the nose, in order toobtain a euphoric “high,” a sufficient amount of the opioid antagonistwould thereby be released to antagonize the opioid agonist and toneutralize or block its intended euphoric, analgesic effect.

Depending upon the specific opioid antagonist(s) present in theembodiment of the oral dosage form of the present invention, the dose ofthe opioid antagonist(s) will vary. For example, a single 50 mg dose ofnaltrexone is generally sufficient to block the analgesic effect of anopioid agonist. See, e.g., U.S. Pat. Nos. 6,228,863 and 6,277,384. Thedosage amount of any of the opioid antagonists which can be used inaccordance with the invention can readily be determined by one ofordinary skill in the art. As mentioned above, the dosage amount of theopioid antagonist will be at least that amount of the opioid antagonistwhich is sufficient to antagonize the opioid agonist and thuseffectively neutralize the intended analgesic effect of the opioidagonist.

The invention provides an oral dosage form which does not release atherapeutically effective amount of an opioid antagonist when the oraldosage form is orally administered to a human being. That is, the oraldosage form of the invention is designed such that when orallyadministered to a human being, it would not provide effective bloodlevels of the opioid antagonist for up to about twenty-four (24) hoursand beyond, at which time the opioid agonist would have previously beenreleased and would have had its intended analgesic effect on the humanbeing.

According to an embodiment of the invention, the oral dosage formincludes a biologically inert pellet (core) coated first by anopioid-antagonist layer, which is then coated by a non-releasingmembrane. Many types of inert pellets are suitable for use in formingthe core of this embodiment of the oral dosage form, and arecommercially available from a number of companies; for example,non-pareils, sugar and/or starch-based pellets are all suitable types ofpellets. Sugar spheres of particle size 25 to 30 mesh are particularlypreferred, although any inert pellets of mesh size within the range of14 mesh to 60 mesh are also preferred for use in this invention. Inaddition, other substrates, including but not limited to, granules,spheroids and beads, may be used in accordance with this embodiment ofthe invention.

In this embodiment of the invention, an opioid-antagonist layer coatsthe biologically inert pellet of the oral dosage form. Theopioid-antagonist layer comprises a therapeutically effective amount ofan opioid antagonist. Any opioid antagonist, or a pharmaceuticallyacceptable salt thereof, or combinations thereof, may be used inaccordance with the invention. Examples of a suitable opioid antagonist,include but are not limited to, naltrexone, naloxone, and nalmephene.Preferably, the opioid antagonist comprises naltrexone.

The opioid-antagonist layer may also include a binder agent to enhanceits adherence to the biologically inert pellet. Suitable binder agentsfor use in the opioid-antagonist layer of the invention include, but arenot limited to, hydroxypropylmethyl cellulose (HPMC) (3 to 6 cps,preferably 6 cps), hydroxyethyl cellulose, hydroxypropyl cellulose,methyl cellulose, polyvinyl pyrrolidone and the like. Preferably,hydroxypropylmethyl cellulose, and most preferably, hydroxypropylmethylcellulose E6 or Opadry® clear is used in accordance with the invention.Preferably, the binder agent is dissolved in water (or any suitablesolvent) to form a 5% to 30% (w/w) solution, preferably a 7% to 25%(w/w) solution and most preferably, an approximately 10% (w/w) solution.The solution of binder agent is admixed with a solution or suspension ofthe opioid antagonist, and then applied onto the biologically inertpellets by conventional spray techniques. For example, the opioidantagonists/binder agent solution or suspension may be applied to thebiologically inert pellets by spraying the solution or suspension ontothe pellets using a fluid bed processor. Preferably, the amount ofbinder agent included in the opioid-antagonist layer is in a ratio ofbinder agent to opioid-antagonist of about 1:10, although any ratio issuitable for use with the present invention.

The opioid-antagonist layer of this embodiment of the oral dosage formof the present invention may also include one or more pharmaceuticallyacceptable excipients in addition to the opioid antagonist and theoptional binder agent. Suitable pharmaceutically acceptable excipientswhich may be employed in the invention are well known to those ofordinary skill in the art and include any conventional pharmaceuticallyacceptable excipient, such as an antifoam agent, which is added to aidthe formulation process. The opioid-antagonist layer may also include asuitable carrier, diluent, surfactant and/or lubricant.

In another embodiment of the invention, the opioid-antagonist layer iscoated with an optional sealing layer. The sealing layer contains awater soluble polymer, which may be the same or different from thebinder agent present in the opioid-antagonist layer. For example, thesealing layer may include a water soluble polymer such ashydroxypropylmethyl cellulose (3 to 6 cps, preferably 6 cps),hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,polyvinylpyrrolidone and the like. Preferably, hydroxypropylmethylcellulose, and most preferably, hydroxypropylmethyl cellulose-E-6 isemployed in the sealing layer. In addition, the sealing layer mayoptionally contain a lubricant, such as for example, calcium stearate,magnesium stearate, zinc stearate, stearic acid, talc or a combinationthereof. The total amount of this optional sealing layer contained inthe finally coated pellets is preferably about 0.5% to about 5% of thetotal weight of the finally coated pellet.

In a further embodiment of the invention, the oral dosage form includesan opioid-antagonist formulation comprising a therapeutically effectiveamount of an opioid antagonist, which is then coated by a non-releasingmembrane. In this embodiment of the invention, the opioid-antagonistformulation may be produced by any method known in the art, includingbut not limited to, forming a matrix system of the opioid antagonistwhich would then be compressed into a tablet. Furthermore, theopioid-antagonist formulation may be provided in any form known in theart, including but not limited to, pellets, granules, spheroids,capsules and tablets. As would be understood by one of ordinary skill inthe art, such an opioid-antagonist formulation could further include,for example, binder agents, diluents, carriers, fillers, lubricants andother pharmaceutically acceptable additives and excipients which areused in the formation of the particular form of the formulation, and allsuch opioid-antagonist formulations are within the scope of the presentinvention. In further embodiments of the invention, theopioid-antagonist formulation may be coated with an optional sealinglayer prior to coating with the non-releasing membrane.

According to the present invention, the oral dosage form also includes anon-releasing membrane which is coated onto the opioid-antagonist layer,the opioid-antagonist formulation, or the optional sealing layer,depending upon the particular embodiment of the oral dosage form. Thenon-releasing membrane serves to protect the integrity of thebiologically inert pellets coated with the opioid-antagonist layer, orthe opioid-antagonist formulation, such that the therapeuticallyeffective amount of the opioid antagonist is not released from the oraldosage form when it is orally administered to a human being. At the sametime however, if the oral dosage form is physically altered and thenon-releasing membrane is rendered ineffective, then the therapeuticallyeffective amount of the opioid antagonist is thereby released from theoral dosage form.

The non-releasing membrane of the invention comprises a water-retardantpolymer, such as, for example, an alkyl cellulose, an acrylic acidpolymer, an acrylic acid copolymer, a methacrylic acid polymer, amethacrylic acid copolymer, shellac, zein, or hydrogenated vegetableoil. The water-retardant polymer is physiologically acceptable, and itsubstantially prevents the release of the opioid antagonist. Inaddition, the water-retardant polymer could optionally be waterinsoluble. A preferred water-retardant polymer is a poly(meth)acrylatepolymer, such as Eudragit NE 30 D or Eudragit NE 40 D, or a combinationthereof. Most preferably, the water-retardant polymer comprises thepoly(meth)acrylate polymer, Eudragit NE 30 D. Eudragit NE 30 D andEudragit NE 40 D polymers are available from Rhom Pharma, D-6108Weiterstadt 1, Dr. Otto-Rohm-Str. 2-4, Germany. Eudragit NE 30 D andEudragit NE 40 D are pH independent polymers available as 30% or 40%aqueous dispersions, respectively. Furthermore, Eudragit RS 30 D,Eudragit RL 30 D, Eudragit S and Eudragit L 30 D are further examples ofsuitable water-retardant polymers. When employing Eudragit NE 30 D asthe water-retardant polymer, the NE30D solids in the non-releasingmembrane generally constitute about 15% to about 80% of the total weightof the solids content of the final oral dosage form, preferably about25% to about 60%, and most preferably about 30% to about 50% of thetotal weight of the solids content of the final oral dosage form.

In a preferred embodiment of the present invention, the non-releasingmembrane contains in addition to a water-retardant polymer, an amount ofa lubricant, such as for example, calcium stearate, magnesium stearate,zinc stearate, stearic acid, talc or a combination thereof, to form thenon-releasing membrane. In particular, it is preferred that thenon-releasing membrane contains an amount of magnesium stearate, orother lubricant, sufficient to provide non-release of the opioidantagonist for up to about 14-24 hours after administration of thedosage form to a human being. In a most preferred embodiment, thenon-releasing membrane contains magnesium stearate admixed with thewater-retardant polymer, which is preferably Eudragit NE30D. Inembodiments of the invention including opioid-antagonist-coated pellets,the lubricant functions to prevent agglomeration of theopioid-antagonist-coated pellets during processing and also helps toprevent release of the opioid antagonist from theopioid-antagonist-coate-d pellets. Preferably, the final, driednon-releasing membrane contains about 5% to about 50% magnesium stearateand/or other lubricant(s), and more preferably about 7% to about 30%,and most preferably about 10% to about 25% lubricant(s) based on thetotal weight of solids content of the total formulation.

In another embodiment of the invention, the non-releasing membrane iscoated with an optional sealing layer. This optional sealing layer issimilar to the previously described optional sealing layer between, forexample, the opioid-antagonist layer and the non-releasing membrane, andin fact may be comprised of the same exact elements. Thus, the sealinglayer contains a water soluble polymer, which may be the same ordifferent from the binder agent present in the opioid-antagonist layer.For example, the sealing layer may include a water soluble polymer suchas hydroxypropylmethyl cellulose (3 to 6 cps, preferably 6 cps),hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,polyvinylpyrrolidone and the like. Preferably, hydroxypropylmethylcellulose, and most preferably, hydroxypropylmethyl cellulose-E-6 isemployed in the sealing layer. In addition, the sealing layer mayoptionally contain a lubricant, such as for example, calcium stearate,magnesium stearate, zinc stearate, stearic acid, talc or a combinationthereof. In embodiments of the invention employing pellets, the totalamount of this optional sealing layer contained in the finally coatedpellets is preferably about 0.5% to about 10% of the total weight of thefinally coated pellet. In further embodiments of the invention, theoptional sealing layer may also be coated with an enteric layer.

In a further embodiment of the invention, the non-releasing membrane iscoated with an enteric layer comprising an enteric coating polymer, andoptionally comprising a plasticizer. A preferred enteric coating polymeris Eudragit L 30D. Suitable plasticizers for inclusion in the entericlayer include, for example, triethyl citrate, polyethylene glycol,dibutyl phthalate, diethylphthalate and triacetin. In embodiments of theinvention employing pellets, the optional enteric layer, which is pHdependant and resistant to gastric fluids, preferably comprises fromabout 0.5% to about 10% of the total weight of the finally coatedpellet. In further embodiments of the invention, the enteric layer mayalso be coated with a sealing layer.

In another embodiment of the invention, the non-releasing membrane(optionally coated with an enteric layer and/or a sealing layer) iscoated with an opioid-agonist layer comprising an opioid agonist. Anyopioid agonist, or a pharmaceutically acceptable salt thereof, may beused in accordance with the invention. Examples of the opioid agonistwhich may be included in this embodiment of the invention include, butare not limited to, oxycodone, hydrocodone, morphine, hydromorphone,codeine, and mixtures thereof. Preferably, the opioid agonist comprisesoxycodone. In further embodiments of the invention, the opioid-agonistlayer may also be coated with a sealing layer and/or an enteric layer.

In the present invention, the opioid agonist is preferably present in anamount which will provide for effective blood levels of the opioidagonist in a human being. That is, when the oral dosage form of theinvention is orally administered to a human being, the opioid agonistwill be released from the oral dosage form, and it can thus have itsintended analgesic effect upon the human being. This is because, asdescribed above, upon oral administration of the oral dosage form of theinvention, the opioid antagonist will not be sufficiently released fromthe oral dosage form, thereby enabling the opioid agonist to have itsintended analgesic effect. At the same time, however, if the oral dosageform of the invention is physically altered in any way, such as bygrinding or crushing, then the therapeutically effective amount of theopioid antagonist will be released from the oral dosage form, therebyantagonizing the opioid agonist and thus effectively neutralizing theintended analgesic effect of the opioid agonist. Thus, the formation ofthe oral dosage form of the invention is an effective method ofpreventing the abuse of an oral dosage form of an opioid agonist. Forexample, if an individual were to crush and grind up the oral dosageform of the present invention in an attempt to take it parenterally,orally, or by snorting it through the nose, in order to obtain aeuphoric “high”, a sufficient amount of the opioid antagonist wouldthereby be released to antagonize the opioid agonist and to neutralizeor block its intended euphoric, analgesic effect.

In addition, the opioid-agonist layer of this embodiment may furtherinclude, for example, binder agents, diluents, carriers, fillers,lubricants and other pharmaceutically acceptable additives andexcipients which may or may not effect the rate of release of the opioidagonist from the oral dosage form of this embodiment. Thus, any type ofrelease profile known in the art, including but not limited to,immediate and sustained release formulations, may be used in accordancewith the opioid-agonist layer of this embodiment.

The opioid-antagonist layer, the opioid-antagonist formulation, and/orthe non-releasing membrane of the invention may each further comprisediluents, carriers, fillers and other pharmaceutical additives which mayor may not effect the rate of release of the opioid antagonist from theoral dosage form of the invention. For example, the non-releasingmembrane preferably contains a lubricant and the opioid-antagonist layermay optionally contain a surfactant. The opioid-antagonist layer, theopioid-antagonist formulation, and/or the non-releasing membrane mayalso further contain pharmaceutically acceptable excipients such asanti-adherents, and pharmaceutically acceptable pigments such astitanium dioxide, iron oxide and various color pigments includingvegetable dyes, and the like.

In embodiments of the invention employing pellets, the opioid-antagonistloaded pellets preferably provide in total a potency of about 6% toabout 70% (w/w) based upon the total weight of the layered pellets,although the potency can be adjusted as desired. For example, when theopioid antagonist employed in the invention is naltrexone, it ispreferred that the layered pellets be formulated at about 60% potency(w/w). However, the skilled practitioner can formulate the oral dosageforms of the invention to have any desired total potency of opioidantagonist.

The non-release, oral dosage form of the invention, as disclosed herein,is designed such that it does not provide for effective blood levels ofthe opioid antagonist for at least 24 hours after oral administration ofthe oral dosage form. In addition, the non-release, oral dosage formprovides a dissolution rate of the opioid antagonist, when measured invitro by the U.S. Pharmacopeia XXVI basket method of 100 rpm in 900 mlof water at 37° C., wherein the therapeutically effective amount of theopioid antagonist is not released from the dosage form after about 14 to24 hours.

The process for making an embodiment of the oral dosage form of theinvention includes coating at least one layer of an opioid antagonistonto the surface of a biologically inert pellet (e.g., a non-pareilpellet (sugar and/or starch-based pellets)) to form opioid-antagonistloaded pellets. The opioid-antagonist loaded pellets are then coatedwith a non-releasing membrane.

In preparing an embodiment of the oral dosage form of the invention, theopioid-antagonist layer may be applied by spraying the opioid-antagonistsuspension onto sugar spheres or other biologically inert pellets thathave been suspended in a fluidized bed, for example. Other conventionalspray techniques such as pan coating may also be used. Theopioid-antagonist loaded pellets can also be prepared by anextruder/marumerizer. After the sugar spheres or pellets are coated withthe opioid-antagonist layer, they may optionally be dried by airexposure, or other methods known in the art (although drying may occurspontaneously from air flow in the fluid bed processor).

In this embodiment, the non-releasing membrane including thewater-retardant polymer is next coated onto the opioid-antagonist loadedpellets. The water-retardant polymer comprising the non-releasingmembrane is generally prepared as a dispersion and sprayed onto theopioid-antagonist loaded pellets. The total amount of water-retardantpolymer in the pellets is in the range of from about 15% to about 80% ofthe total weight of the prepared pellets, preferably about 30% to about55% of the total weight of the prepared pellets. By varying the amountof water-retardant polymer within this range, the desired non-release ofthe opioid antagonist is achieved.

At the final stage in preparing this embodiment, the coated pellets mayoptionally be subjected to a curing process. For example, the coatedpellets may be cured at a temperature in the range of from about 30° toabout 50° C., preferably from about 35° to about 45° C., and mostpreferably about 40° C., for a period of about 5 to about 10 days and,preferably, about 7 days. A further example of a suitable curing processcould be performed in a fluid bed processor for about 1 to about 5 hoursat about 40° to about 80° C., preferably for about 3 hours at about 55°to about 65° C., and most preferably for about 1 hour at about 60° C.

The coated pellets may then be weighed out according to the total doseof opioid antagonist to be administered to patients. Diluent may beadded, such as, for example, dextrose, sorbitol, mannitol,microcrystalline cellulose, methocel ether, lactose, glycerylpalmitostearate, glyceryl stearate, glyceryl behenate, and combinationsthereof, among other commonly used pharmaceutical diluents, and themixture of coated pellets and diluents pressed into tablets.Alternatively, the coated pellets, with or without diluents, can beencapsulated in a capsule, such as a hard gelatin capsule. Furthermore,in an embodiment of the invention, the opioid agonist(s) can also beadded to a tablet or capsule containing the opioid-antagonist loadedpellets.

It is often desirable to add inert diluent when formulating the coatedpellets into tablet form. The presence of pharmaceutical diluents, suchas microcrystalline cellulose, methocel ether, glyceryl palmitostearate,glyceryl stearate, and/or glyceryl behemate, for example, in the coatedpellet mixture serves to cushion the pellets so that they are notsignificantly ruptured during compression. In addition, pharmaceuticaldiluents can be added to enhance the non-releasing property of the oraldosage form of the present invention.

In general, the release rate of opioid antagonist from the coatedpellets is dependent upon a number of factors including, inter alia, theoverall structure and design of the coated pellet, the potency of thecoated pellet, the type and amount of water-retardant polymer present inthe non-releasing membrane, and when present in the coated pellets, thetype and amount of lubricant. The coated pellets may be formulated intotablets or encapsulated in the desired dosage amount. Typical unitdosage amounts for the opioid antagonist of the oral dosage form of theinvention include any dosage between about 1 and 200 mg, althoughdosages outside of this range may also be employed in the presentinvention.

In another embodiment of the oral dosage form of the invention, inaddition to the coated pellets described above which are coated with anopioid antagonist, the oral dosage form may include an opioid-agonistformulation including an opioid agonist. The opioid-agonist formulationmay be produced by any method known in the art, including the methoddescribed above wherein pellets are coated by use of a fluid bedprocessor. In addition, the opioid-agonist formulation may be providedin any form known in the art, including but not limited to, pellets,granules, spheroids, capsules and tablets, with any type of releaseprofile, including but not limited to, immediate and sustained releaseformulations. Any opioid agonist, combinations thereof, or apharmaceutically acceptable salt thereof, may be used in accordance withthe invention. Examples of the opioid agonist which may be included inthe oral dosage form of the invention include, but are not limited to,oxycodone, hydrocodone, morphine, hydromorphone, codeine, and mixturesthereof. Preferably, the opioid agonist comprises oxycodone.

In this embodiment of the invention, the opioid agonist is preferablypresent in an amount which will provide for effective blood levels ofthe opioid agonist in a human being. That is, when this embodiment ofthe oral dosage form of the invention is orally administered to a humanbeing, the opioid agonist will be released from the oral dosage form,and it can thus have its intended analgesic effect upon the human being.This is because, as described above, upon oral administration of theoral dosage form of the invention, the opioid antagonist will not besufficiently released from the oral dosage form, thereby enabling theopioid agonist to have its intended analgesic effect. At the same time,however, if this embodiment of the oral dosage form of the invention isphysically altered in any way, such as by grinding or crushing, then thetherapeutically effective amount of the opioid antagonist will bereleased from the oral dosage form, thereby antagonizing the opioidagonist and thus effectively neutralizing the intended analgesic effectof the opioid agonist. Thus, the formation of the oral dosage form ofthis embodiment is an effective method of preventing the abuse of anoral dosage form of an opioid agonist. For example, if an individualwere to crush and grind up the oral dosage form of the present inventionin an attempt to take it parenterally, orally, or by snorting it throughthe nose, in order to obtain a euphoric “high”, a sufficient amount ofthe opioid antagonist would thereby be released to antagonize the opioidagonist and to neutralize or block its intended euphoric, analgesiceffect.

The following examples are illustrative of the invention, and are not tobe construed as limiting the invention in any way.

EXAMPLES

In these examples, embodiments of the oral dosage form of the inventionwere prepared as follows.

Step 1: Applying an Opioid Antagonist Layer to a Biologically InertPellet

Ingredients

Example 1 Example 2 naltrexone hydrochloride   50 grams  531 gramshydroxypropylmethyl cellulose (HPMC)   50 grams  530 grams (methocel E610% solution) (i.e., 90% water) purified water   175 grams 1050 gramssimethicone 30% emulsion (i.e., 70% water)    1 gram  10 grams 25/30mesh sugar spheres   750 grams  413 grams total weight: 805.3 grams 1000grams Note: the water is evaporated during this process and is thus notpart of the total weight.

Method

An opioid-antagonist suspension was prepared by mixing the methocel E610% solution (binder agent), the naltrexone hydrochloride (opioidantagonist), the simethicone 30% emulsion (antifoam agent) and thepurified water (in the amounts listed above for each example). Thisopioid-antagonist suspension was then sprayed onto the 25/30 mesh sugarspheres using a fluid bed processor, resulting in biologically inertpellets coated with an opioid-antagonist layer. In Example 1, thesecoated pellets have a naltrexone (opioid antagonist) potency of 6.2%,and in Example 2, these coated pellets have a naltrexone (opioidantagonist) potency of 53%.

Step 2: Applying a Non-Releasing Membrane to the Coated Pellets ofExample 1 from Step 1

Ingredients

coated pellets of Example 1 from step 1 650 grams Eudragit NE 30D 30%dispersion 700 grams magnesium stearate 15% suspension 560 grams

Method

Next, the Eudragit NE 30D 30% dispersion and the magnesium stearate 15%suspension (in the amounts listed above) were added together and mixedto form a non-releasing suspension. This non-releasing suspension wasthen sprayed onto 650 grams of the coated pellets of Example 1 from step1 using a fluid bed processor. These twice-coated pellets were thencured in the fluid bed processor for about 6 hours at 60° C.

Step 3: Filling into Capsules

The coated pellets from step 2 were then filled into capsules to give aneffective dose of 50 mg naltrexone hydrochloride.

Step 4: In-Vitro Dissolution Testing

Dissolution testing was then performed on the capsules prepared in step3 as described above. In this example, the Eudragit NE 30D solidscoating constituted 42.48% of the final formulation (i.e., the capsule),and the total solids coating constituted 59% of the final formulation(i.e., the capsule). As used herein, the “total solids coating” refersto the Eudragit NE 30D and the magnesium stearate, as described above instep 2. The conditions for testing were those of the USP Basket Methodof 100 rpm in 900 ml of de-ionized water at 37° C., with the resultsshown below in Table 1. A graph of these in vitro dissolution testingresults can be seen in FIG. 1.

TABLE 1 Dissolution Data Time (in hours) Percentage of NaltrexoneReleased 0 0 1 0 2 0.1 3 0.1 4 0.5 6 0.5 8 0.4 10 0.5 12 0.5 14 0.7 160.9 18 1.4 20 2.4 22 3.9 24 5.7

As can be seen from Table 1 above, in this embodiment of the oral dosageform of the invention, the therapeutically effective amount of thenaltrexone is still not released from the dosage form after about 14 to24 hours, as only 5.7% of the naltrexone has been released from thedosage form after about 24 hours. Thus, in this example, 5.7% of the 50mg naltrexone (i.e., about 2.85 mg) has been released after about 24hours, which is insufficient to block or neutralize the intendedanalgesic effect of an opioid agonist.

It should be understood that some modification, alteration andsubstitution is anticipated and expected from those skilled in the artwithout departing from the teachings of the invention. Accordingly, itis appropriate that the following claims be construed broadly and in amanner consistent with the scope and spirit of the invention.

1. An oral dosage form comprising: a biologically inert pellet; anopioid-antagonist layer coated on the biologically inert pellet, whereinthe opioid-antagonist layer comprises a therapeutically effective amountof an opioid antagonist; and a non-releasing membrane coated on theopioid-antagonist layer, wherein the non-releasing membrane comprises atleast one water-retardant polymer that is a EUDRAGIT® NE 30D or NE 40Dnon-ionic poly(ethyl acrylate-co-methyl methacrylate), wherein less thana therapeutically effective amount of the opioid antagonist is releasedfrom the dosage form after about 14 to 24 hours in vitro, when measuredby the USP Basket method at 100 rpm in 900 ml of water at 37° C.
 2. Theoral dosage form of claim 1, wherein the opioid antagonist comprisesnaltrexone.
 3. The oral dosage form of claim 1, wherein thenon-releasing membrane further comprises a lubricant.
 4. The oral dosageform of claim 3, wherein the lubricant comprises a member selected fromthe group consisting of calcium stearate, magnesium stearate, zincstearate, stearic acid, talc and a combination thereof.
 5. The oraldosage form of claim 1, wherein the opioid-antagonist layer furthercomprises a binder agent.
 6. The oral dosage form of claim 5, whereinthe binder agent comprises a member selected from the group consistingof hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, methyl cellulose and polyvinyl pyrrolidone.
 7. The oraldosage form of claim 1, further comprising a sealing layer between theopioid-antagonist layer and the non-releasing membrane.
 8. The oraldosage form of claim 1, further comprising at least one of an entericlayer and a sealing layer coated on the non-releasing membrane.
 9. Anoral dosage form including: a first pellet comprising: a biologicallyinert pellet; an opioid-antagonist layer coated on the biologicallyinert pellet, wherein the opioid-antagonist layer comprises atherapeutically effective amount of an opioid antagonist; and anon-releasing membrane coated on the opioid-antagonist layer, whereinthe non-releasing membrane at least one water-retardant polymer that isa EUDRAGIT® NE 30D or NE 40D non-ionic poly(ethyl acrylate-co-methylmethacrylate), wherein less than a therapeutically effective amount ofthe opioid antagonist is released from the dosage form after about 14 to24 hours in vitro, when measured by the USP Basket method at 100 rpm in900 ml of water at 37° C.; and a second pellet comprising an opioidagonist.
 10. The oral dosage form of claim 9, wherein the opioid agonistcomprises oxycodone, and the opioid antagonist comprises naltrexone. 11.The oral dosage form of claim 9, wherein the non-releasing membranefurther comprises a lubricant.
 12. The oral dosage form of claim 11,wherein the lubricant comprises a member selected from the groupconsisting of calcium stearate, magnesium stearate, zinc stearate,stearic acid, talc and a combination thereof.
 13. The oral dosage formof claim 9, wherein the opioid-antagonist layer further comprises abinder agent.
 14. The oral dosage form of claim 13, wherein the binderagent comprises a member selected from the group consisting ofhydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, methyl cellulose and polyvinyl pyrrolidone.
 15. The oraldosage form of claim 9 in a capsule or a tablet form.
 16. The oraldosage form of claim 9, further comprising a sealing layer between theopioid-antagonist layer and the non-releasing membrane.
 17. The oraldosage form of claim 9, further comprising at least one of an entericlayer and a sealing layer coated on the non-releasing membrane.
 18. Anoral dosage form comprising: an opioid-antagonist formulation, whereinthe opioid-antagonist formulation comprises a therapeutically effectiveamount of an opioid antagonist; and a non-releasing membrane coated onthe opioid-antagonist layer, wherein the non-releasing membranecomprises at least one a water-retardant polymer that is a EUDRAGIT® NE30D or NE 40D non-ionic poly(ethyl acrylate-co-methyl methacrylate),wherein less than a therapeutically effective amount of the opioidantagonist is released from the dosage form after about 14 to 24 hoursin vitro, when measured by the USP Basket method at 100 rpm in 900 ml ofwater at 37° C.
 19. The oral dosage form of claim 18, wherein the opioidantagonist comprises naltrexone.
 20. The oral dosage form of claim 18,wherein the non-releasing membrane further comprises a lubricant. 21.The oral dosage form of claim 20, wherein the lubricant comprises amember selected from the group consisting of calcium stearate, magnesiumstearate, zinc stearate, stearic acid, talc and a combination thereof.22. The oral dosage form of claim 18, further comprising a sealing layerbetween the opioid-antagonist formulation and the non-releasingmembrane.
 23. The oral dosage form of claim 18, further comprising atleast one of an enteric layer and a sealing layer coated on thenon-releasing membrane.